EP2029106A2 - Schäumbare trägersubstanz mit polypropylenglycolalkylether und pharmazeutische zusammensetzungen daraus - Google Patents

Schäumbare trägersubstanz mit polypropylenglycolalkylether und pharmazeutische zusammensetzungen daraus

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Publication number
EP2029106A2
EP2029106A2 EP07848880A EP07848880A EP2029106A2 EP 2029106 A2 EP2029106 A2 EP 2029106A2 EP 07848880 A EP07848880 A EP 07848880A EP 07848880 A EP07848880 A EP 07848880A EP 2029106 A2 EP2029106 A2 EP 2029106A2
Authority
EP
European Patent Office
Prior art keywords
agent
foamable
oil
therapeutic composition
agents
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07848880A
Other languages
English (en)
French (fr)
Inventor
Doron Freidman
Dov Tamarkin
Naomi Feiman
David Schuz
Tal Berman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Foamix Ltd
Original Assignee
Foamix Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/481,596 external-priority patent/US8119150B2/en
Priority claimed from US11/488,989 external-priority patent/US10117812B2/en
Priority claimed from US11/717,897 external-priority patent/US8119109B2/en
Application filed by Foamix Ltd filed Critical Foamix Ltd
Publication of EP2029106A2 publication Critical patent/EP2029106A2/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/16—Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/046—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/008—Preparations for oily skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/006—Antidandruff preparations

Definitions

  • This invention relates to foamable pharmaceutical and cosmetic compositions and foams, in particular poly(propylene) glycol ("PPG") alkyl ether comprising foamable pharmaceutical and cosmetic compositions and foams.
  • PPG poly(propylene) glycol
  • External topical administration is an important route for the administration of drugs in disease treatment.
  • Many groups of drugs including, for example, antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic, antiallergic, corticosteroid, retinoid and anti-proliferative medications are preferably administered in hydrophobic media, namely ointment.
  • ointments often form an impermeable barrier, so that metabolic products and excreta from the wounds to which they are applied are not easily removed or drained away.
  • Foams are considered a more convenient vehicle for topical delivery of active agents.
  • topical foams including aqueous foams, such as commonly available shaving foams; hydroalcoholic foams, such as described in U.S. Patent No.
  • emulsion-based foams comprising oil and water components, such as described in U.S. Patent No. 6,730,288 and WO 2004/037225; and oleaginous foams, which consist of high oil content, such as described in U.S. Patent Application No. US 2005/0031547.
  • oil containing foams are preferred, since oil contributes to skin protection and moisturization, which improve the therapeutic effect of the formulation.
  • foams are made using liquefied hydrocarbon gas propellant, such a spropane, butane and isobutane.
  • U.S. Patent No. 6,001,341 discloses deodorant and/or antiperspirant cosmetic compositions comprising an alkyl ester or a mixture of alkyl esters wherein the carrying agents can be ethers of mono- and poly-hydroxylic alcohols or their mixtures such as, for example, dimethylisosorbide, di-isopropylether; polypropyleneglycol (PPG-10 cetyl ether, PPG-14 butyl ether, PPG-27 glyceryl ether).
  • PPG-10 cetyl ether PPG-14 butyl ether
  • PPG-27 glyceryl ether PPG-15 stearyl ether and/or foams thereof are exemplfied therein.
  • U.S. Patent No. 5,614,178 discloses a water-based topical pharmaceutical composition having enhanced penetration through the skin, comprising from about 0.1% to about 25% of an alkoxylated ether, such as PPG- 14 butyl ether, PPG-15 stearyl ether, and mixtures thereof, in addition to a safe and effective amount of a pharmaceutical active agent, from about 0.1% to about 10.0% of a high molecular weight crosslinked cationic polymer, and from about 0.05% to about 5% of a high HLB non-ionic surfactant.
  • U.S. Patent No. 5,614,178 does not teach or suggest preparing foams comprising PPG.
  • U.S. Patent No. 5,614,178 does not teach or suggest preparing compositions containing high amounts of PPG
  • WO 98/52536 discloses a skin care composition comprising a retinoid and a preservative, and further optionally comprising a carrier.
  • PPG ethers are, inter alia, mentioned therein as possible ingredients in the carrier, but foams in general and PPG foams in particular, are neither taught nor suggested.
  • U.S. Patent No. 4,083,974 discloses a topically applied pharmaceutical composition in an ointment form, which contain an effective amount of an antiinflammatory steroid and 1-40 % of polyoxypr ⁇ pylene 15 stearyl ether. Further are disclosed therein nonaqueous solutions and oinments for topical application, which comprise an effective amount of an anti-inflammatory steroid and a solubilizing effective amount of polyoxypropylene 15 stearyl ether.
  • an ointment containing about 89% PPG-15 but no surfactant was prepared, but the application of this sample, as well as of any of the other ointments (having 15-40 % PPG-15 stearate), on the skin- is not described. Furthermore, the preparation of foams of any of these compositions is neither taught nor suggested.
  • the present invention relates to PPG alkyl ether comprising foamable compositions and foams.
  • the foamable carrier includes: a polypropylene glycol alkyl ether; a surface-active agent; a solvent; and a liquefied or compressed gas propellant at a concentration of about
  • the foamable carrier includes: a polypropylene glycol alkyl ether of about 3% to about 90% by weight of the total composition; a surface-active agent; a solvent; and a liquefied or compressed gas propellant at a concentration of about
  • the foamable therapeutic composition includes: a therapeutically effective amount of an active agent; a polypropylene glycol alkyl ether of about 3% to about 90% by weight of the total composition; a surface-active agent; a solvent; and a liquefied or compressed gas propellant at a concentration of about
  • the method of treating a disorder of a mammalian subject includes: administering a foamable therapeutic composition to a target site, the composition comprising: a therapeutically effective concentration of an active agent; a polypropylene glycol (PPG) alkyl ether of about 3% to about 90% by weight of the total composition; a surface-active agent; a solvent; and a liquefied or compressed gas propellant at a concentration of about
  • a foamable therapeutic composition comprising: a therapeutically effective concentration of an active agent; a polypropylene glycol (PPG) alkyl ether of about 3% to about 90% by weight of the total composition; a surface-active agent; a solvent; and a liquefied or compressed gas propellant at a concentration of about
  • PPG polypropylene glycol
  • the foamable pharmaceutical carrier includes: at least 15% polypropylene glycol alkyl ether and liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • the foamable therapeutic composition includes: a therapeutically effective amount of an active agent; at least 15% polypropylene glycol alkyl ether and a liquefied or compressed gas propellant at a concentration of about
  • the method of treating a disorder of a mammalian subject includes: administering a foamable therapeutic composition to a target site, the composition comprising: a therapeutically effective concentration of an active agent; at least 15% polypropylene glycol alkyl ether and a liquefied or compressed gas propellant at a concentration of about
  • FIG. 1 is a microscope picture of an exemplary formulation B, according to a preferred embodiment of the present invention, which contains about 60% PPG and about 33% water; and
  • FIG. 2 is a microscope picture of an exemplary formulation A, according to a preferred embodiment of the present invention, which contains about 80% PPG and no water.
  • the present invention relates to a composition for use as foamable vehicle composition.
  • the foamable carrier includes: a) a polypropylene glycol alkyl ether; b) a surface-active agent; c) a solvent; and d) a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • the present invention includes the embodiments described above in the Summary of the invention as more particularly exemplified below,
  • the foamable vehicle further includes a foam adjuvant. More particularly the foam ajuvant is preferably selected from the group consisting of a fatty alcohol; a fatty acid;and a fatty alcohol. [0031] Optionally, the foamable vehicle further includes at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, an organic polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight.
  • the hydrophobic solvent and/or the emollient can be selected from the group consisting of mineral oil, alkyl esters of fatty acids such as isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononano
  • a "polar solvent” is an organic solvent, typically soluble in both water and oil.
  • polar solvents include polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1 -menthol, dioxolane, ethylene glycol, other glycols, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone (1-dodecylazacycloheptan- 2-one), 2-(n-nonyl)-1 ,3-dioxolane, alkanols, such as dialkylamino acetates, and admixtures thereof.
  • PPG Polypropylene glycol
  • a polypropylene glycol alkyl ether is a liquid, water-insoluble propoxylated fatty alcohol, having the molecular formula of RO(CH 2 CHOCH 3 ) n ; wherein 11 R" is a straight- chained or branched C 4 to C 22 alkyl group; and "n" is in the range between 4 and about 50.
  • PPG alkyl ethers are organic liquids that function as skin- conditioning agent in pharmaceutical and cosmetic formulations. They possess exceptional emollient effect, side by side with enhanced solvency properties, which facilitates solubilization of active agents in a composition comprising a PPG alkyl ether.
  • PPG alkyl ethers offer the following advantages when used as a component in the foamable composition of the present invention: - Due to the polypropylene glycol moiety, PPG alkyl ethers possess certain surface active properties and they assist in the coupling of polar and non- polar oils in an emulsion formulation.
  • PPG alkyl ethers are non-occlusive; offering a long-lasting and velvety feel.
  • PPG alkyl ethers When combined with certain surfactants, such as Brij 72 and Brij 721 , PPG alkyl ethers form oleosomes and/or liquid crystal structures, which provide long lasting moisturization, excellent spreading as well as prolonged hydration properties
  • Exemplary PPG alkyl ethers include PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether
  • Preferred PPG alky ethers according to the present invention include PPG-15 stearyl ether (also known as Earlamol E ® , Unichema), PPG-2 butyl ether, PPG-9-13 butyl ether and PPG-40 butyl ether.
  • PPG alkyl ethers can be incorporated in the foamable composition of the present invention in a concentration between about 1% and about 90%, more preferably above 15%, above 20%, above 30% .. .and up to 60% PPG.
  • PPG alkyl ethers also reduce the degree of inflammability of a foam, as demonstrated in a standard inflammability test according to European Standard prEN 14851 , titled "Aerosol containers - Aerosol foam flammability test" was performed on foam compositions PPG 1 and PPG 5. According to this standard, a product is considered inflammable if a stable flame appears following ignition, which is at least 4 cm high and which is maintained for at least 2 seconds. Thus, in an embodiment of the present invention the foamable composition, which contains a PPG alkyl ether is non-flammable, when tested according to European Standard prEN 14851. In additional embodiments, the concentration of the PPG alkyl ether is sufficient to reduce the degree of inflammability, when compared with the same composition where the oil component comprises an another oil, such as mineral oil or an ester of a fatty acid.
  • the oil component comprises an another oil, such as mineral oil or an ester of a fatty acid.
  • PPG stearyl ethers function as skin-conditioning and penetration agents in cosmetic formulations.
  • Polypropylene glycol stearyl ether 15 also known as polyoxypropylene
  • PPG-15 15 stearyl ether or as "PPG-15", and having a CAS Registry No. of [25231-21-4], is a stearyl ether having about 15 propylene oxide units incorporated in its structure.
  • PPG-15 stearyl ether is a clear liquid, soluble in mineral oil, isopropyl ethers, cottonseed oil, ethanol, isopropanol and hexadecyl alcohol, to name a few, and is particularly useful as a solvent of difficult to formulate ingredients, such as sunscreens, aluminum chiorhydrate salts and skin toners. It is insoluble in water, propylene glycol and glycerin.
  • PPG-15 stearyl ether is an inert and highly stable compound.
  • PPG stearyl ether has been known to form liquid crystal structures known as "oleosomes", which are oil-in-water emulsions having multiple layers of water, emollient and emulsifier. Such structures may offer several benefits in the preparation of cosmetical or pharmaceutical formulations in that they improve the dissolution of poorly water-soluble drug, the ability to control the release of drugs and/or the ability to protect and facilitate the transport of "fragile" molecules.
  • PPG stearyl ether also functions as a coupling agent, allowing, for example, the compatibility of polar and non polar oils with ethanol and perfumes in after shave lotions. It is chemically stable at extreme pH levels and at the same time saturated, providing excellent shelf life stability.
  • oleosomes are effective to formulate ingredients such as salts (as in the case of the antiperspirant), extreme pH (found in formulations using alpha and beta hydroxy acids and depilatory formulations) or formulations requiring a high level of alcohol (such as refreshing body milk or aftershaves).
  • the extra layers of water and oil in an oleosome offers noticeable benefits in the areas of skin feel and moisturization.
  • Oleosomes have a luxurious feel when introduced to the skin and excellent subsequent rubout characteristics.
  • the bound water in the oleosome offers long lasting moisturization potential as well.
  • the composition of the present invention contains a polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent.
  • a polymeric agent enhances the creation of foam having fine bubble structure, which does not readily collapse upon release from the pressurized aerosol can.
  • the polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ.
  • Exemplary polymeric agents include, in a non-limiting manner, naturally-occurring polymeric materials, such as locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid; chemically modified starches and the like, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like.
  • naturally-occurring polymeric materials such as locust bean gum, sodium alginate, sodium
  • Additional exemplary polymeric agents include semi-synthetic polymeric materials such as cellulose ethers, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941 , Carbopol® 980 and Carbopol® 981.
  • cellulose ethers such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyeth
  • Polyethylene glycol having molecular weight of 1000 or more (e.g., PEG 1 ,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacity and while they are considered herein as "secondary polar solvents", as detailed herein, they are also considered polymeric agents. [0045] Mixtures of the above polymeric agents are contemplated. [0046] The concentration of the polymeric agent should be selected so that the composition, after filling into aerosol canisters, is flowable, and can be shaken in the canister. In one or more embodiments, the concentration of the polymeric agent is selected such that the viscosity of the composition, prior to filling of the composition into aerosol canisters, is less than 12,000 CPs, and more preferably, less than 10,000 CPs.
  • the composition of the present invention further contains a surface-active agent.
  • Surface-active agents include any agent linking oil and water in the composition, in the form of emulsion.
  • a surfactant's hydrophilic/lipophilic balance (HLB) describes the emulsifier's affinity toward water or oil.
  • HLB hydrophilic/lipophilic balance
  • the HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an equal balance of both characteristics.
  • Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water (o/w) emulsions.
  • the HLB of a blend of two emulsifiers equals the weight fraction of emulsifier A times its HLB value plus the weight fraction of emulsifier B times its HLB value (weighted average).
  • a single surfactant may suffice.
  • a combination of two or more surfactants is desired.
  • Reference to a surfactant in the specification can also apply to a combination of surfactants or a surfactant system. As will be appreciated by a person skilled in the art which surfactant or surfactant system is more appropriate is related to the vehicle and intended purpose. In general terms a combination of surfactants is usually preferable where the vehicle is an emulsion.
  • a combination of surfactants can be significant in producing breakable forms of good quality. It has been further discovered that the generally thought considerations for HLB values for selecting a surfactant or sufactant combination are not always binding for emulsions and that good quality foams can be produced with a surfactant or surfactant combination both where the HLB values are in or towards the lipophilic side of the scale and where the HLB values are in or towards the hydrophilic side of the scale. Surfactants also play a role in foam formation where the foamable formulation is a single phase composition.
  • the composition contains a single surface active agent having an HLB value between about 2 and 9, or more than one surface active agent and the weighted average of their HLB values is between about 2 and about 9.
  • Lower HLB values may in certain embodiments be more applicable to water in oil emulsions.
  • the composition contains a single surface active agent having an HLB value between about 7 and 14, or more than one surface active agent and the weighted average of their HLB values is between about 7 and about 14.
  • Mid range HLB values may in certain embodiments be more suitable for oil in water emulsions.
  • the composition contains a single surface active agent having an HLB value between about 9 and about 19, or more than one surface active agent and the weighted average of their HLB values is between about 9 and about 19. In a waterless or substantially waterless environment a wide range of HLB values may be suitable.
  • the composition of the present invention contains a non- ionic surfactant.
  • Nonlimiting examples of possible non-ionic surfactants include a polysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21 , brij 721 , brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester of sorbitol and its anhydrides, sorbitan monolaurate, sorbitan monolaurate, a monoglyceride, a diglyceride, isoceteth-20 and mono-, di- and tri-esters of sucrose
  • Non-limiting examples of non-ionic surfactants that have HLB of about 7 to about 12 include steareth 2 (HLB-4.9); glyceryl monostearate/PEG 100 stearate ( Av HLB-11.2); stearate Laureth 4 (HLB-9.7) and cetomacrogol ether (e.g., polyethylene glycol 1000 monocetyl ether).
  • Non-limiting examples of preferred surfactants which have a HLB of 4-19 are set out in the Table below:
  • Polyglycerized Fatty Acids such as: PEG-Sorbitan Fatty Acid Esters
  • the surface active agent is a complex emulgator in which the combination of two or more surface active agents can be more effective than a single surfactant and provides a more stable emulsion or improved foam quality than a single surfactant.
  • the complex emulgator comprises a combination of surfactants wherein there is a difference of about 4 or more units between the HLB values of the two surfactants or there is a significant difference in the chemical nature or structure of the two or more surfactants.
  • surfactant systems are, combinations of polyoxyethylene alkyl ethers, such as Brij 59 / BrijiO; Brij 52 / Brij 10; Steareth 2 / Steareth 20; Steareth 2 / Steareth 21 (Brij 72 / Brij 721); combinations of polyoxyethylene stearates such as Myrj 52 / Myrj 59; combinations of sucrose esters, such as Surphope 1816 / Surphope 1807; combinations of sorbitan esters, such as Span 20 / Span 80; Span 20 / Span 60; combinations of sucrose esters and sorbitan esters, such as Surphope 1811 and Span 60; combinations of liquid polysorbate detergents and PEG compounds, such as Tween 80 / PEG- 40 stearate; methyl glucaso sequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2); liquid crystal systems, such as Arlatone (2121
  • the surfactant is preferably one or more of the following: a combination of steareth-2 and steareth-21 on their own or in combination with GMS; in certain other embodiments the surfactant is a combination of polysorbate 80 and PEG-40 stearate. In certain other embodiments the surfactant is a combination of glyceryl monostearate/PEG 100 stearate. In certain other embodiments the surfactant is a combination of two or more of stearate 21 , PEG 40 stearate, and polysorbate 80. In certain orher embodiments the surfactant is a combination of two or more of laureth 4, span ⁇ O, and polysorbate 80.
  • the surfactant is a combination of two or more of GMS and ceteareth. In certain other embodiments the surfactant is a combination of two or more of steareth 21 , ceteareth 20, ceteth 2 and laureth 4 In certain other embodiments the surfactant is a combination of ceteareth 20 and polysorbate 40 stearate. In certain orther embodiments the surfactant is a combination of span 60 and GMS.
  • the stability of the composition can be improved when a combination of at least one non-ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed.
  • the ratio between the at least one non-ionic surfactant having HLB of less than 9 and the at least one non-ionic surfactant having HLB of equal or more than 9, is between 1:8 and 8:1, or at a ratio of 4:1 to 1 :4.
  • the resultant HLB of such a blend of at least two emulsifiers is preferably between about 9 and about 14.
  • a combination of at least one non- ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed, at a ratio of between 1 :8 and 8:1 , or at a ratio of 4:1 to 1 :4, wherein the HLB of the combination of emulsifiers is preferably between about 5 and about 18.
  • the surface active agent is selected from the group of cationic, zwitterionic, amphoteric and ampholytic surfactants, such as sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate and betaines.
  • amphiphilic molecules can show lyotropic liquid-crystalline phase sequences depending on the volume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase segregation of two incompatible components on a nanometer scale. Soap is an everyday example of a lyotropic liquid crystal. Certain types of surfactants tend to form lyotropic liquid crystals in emulsions interface (oil-in-water) and exert a stabilizing effect. Non limiting examples of surfactants with postulated tendency to form interfacial liquid crystals are: phospholipids, alkyl glucosides, sucrose esters, sorbitan esters. In certain embodiments of the present invention surfactants which tend to form liquid crystals may improve the quality of foams produced from compositions of the present invention.
  • the surfactant is a surfactant or surfactant combination is capable of or which tends to form liquid crystals.
  • the at least one surface active agent is liquid.
  • the at least one surface active agent is solid, semi solid or waxy.
  • the surfactant can be, a surfactant system comprising of a surfactant and a co surfactant, a waxy emulsifier, a liquid crystal emulsifier, an emulsifier which is solid or semi solid at room temperature and pressure, or combinations of two or more agents in an appropriate proportion as will be appreciated a person skilled in the art. Where a solid or semi solid emulsifier combination is used it can also comprise a solid or semi solid emulsifier and a liquid emulsifier.
  • the surface- active agent includes at least one non-ionic surfactant.
  • Ionic surfactants are known to be irritants. Therefore, non-ionic surfactants are preferred in applications including sensitive tissue such as found in most mucosal tissues, especially when they are infected or inflamed. We have surprisingly found that non-ionic surfactants alone can provide formulations and foams of good or excellent quality in the carriers and compositions of the present invention.
  • the composition contains a non-ionic surfactant.
  • the composition includes a mixture of non-ionic surfactants as the sole surface active agent.
  • the foamable composition includes a mixture of at least one non-ionic surfactant and at least one ionic surfactant in a ratio in the range of about 100:1 to 6:1.
  • the non- ionic to ionic surfactant ratio is greater than about 6:1 , or greater than about 8:1 ; or greater than about 14:1 , or greater than about 16:1 , or greater than about 20:1.
  • surface active agent comprises a combination of a non- ionic surfactant and an ionic surfactant, at a ratio of between 1 :1 and 20:1.
  • a combination of a non-ionic surfactant and an ionic surfactant is employed, at a ratio of between 1 :1 and 20:1 , or at a ratio of 4:1 to 10:1 ; for example, about 1 :1 , about 4:1 , about 8:1 , about 12:1 , about 16: land about 20:1 or at a ratio of 4:1 to 10:1, for example, about 4:1, about 6:1 , about 8:1 and about 10:1.
  • the upper amount of surfactant that may be used may be limited by the shakability of the composition.
  • the shakability of the formulation reduces until a limitation point is reached where the formulation becomes non shakable and unsuitable.
  • any effective amount of surfactant may be used provided the formulation remains shakable.
  • the upper limit may be determined by flowability such as in circumstances where the composition is marginally or apparently non shakable.
  • any effective amount of surfactant may be used provided the formulation remains flowable.
  • the amount of surfactant or combination of surfactants is between about 0.05% to about 20%; between about 0.05% to about 15%. or between about 0.05% to about 10%.
  • the concentration of surface active agent is between about 0.2% and about 8%. In a more preferred embodiment the concentration of surface active agent is between about 1% and about 6%.
  • composition as formulated is a substantially non shakable composition it is nevertheless possible as an exception in the scope of the present invention for the formulation to be flowable to a sufficient degree to be able to flow through an actuator valve and be released and still expand to form a good quality foam.
  • This surprising and unusual exception may be due one or more of a number of factors such as the high viscosity, the softness, the lack of crystals, the pseudoplastic or semi pseudo plastic nature of the composition and the dissolution of the propellant into the petrolatum.
  • the surface- active agent includes mono-, di- and tri-esters of sucrose with fatty acids (sucrose esters), prepared from sucrose and esters of fatty acids or by extraction from sucro-glycerides.
  • sucrose esters include those having high monoester content, which have higher HLB values.
  • the foamable composition is substantially alcohol-free, i.e., free of short chain alcohols.
  • Short chain alcohols having up to 5 carbon atoms in their carbon chain skeleton and one hydroxyl group, such as ethanol, propanol, isopropanol, butaneol, iso-butaneol, t- butaneol and pentanol, are considered less desirable solvents or polar solvents due to their skin-irritating effect.
  • the composition is substantially alcohol- free and includes less than about 5% final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1%.
  • the active agent degrades in the presence of water, and therefore, in such cases the present of water in the composition is not desirable.
  • the composition is substantially non-aqueous.
  • the term "substantially non-aqueous” or “substantially waterless” is intended to indicate that the composition has a water content below about 5%, preferably below about 2%, such as below about 1.5%. In certain other preferred embodiments the composition is non aqueous or waterless.
  • non aqueous or waterless is meant that the composition contains no or substantially no, free or unassociated or absorbed water.
  • waterless solvents and substances miscible with them of the present invention can be hydrophilic and can contain water in an associated or unfree or absorbed form and may absorb water from the atmosphere and the ability to do so is its hygroscopic water capacity. It is intended that essentially non-aqueous formulations are included within its scope such that the formulations may have present a small amount of water.
  • the composition ingredients are pretreated to reduce, remove or eliminate any residual or associated or absorbed water. Shakability
  • 'Shakability' means that the composition contains some or sufficient flow to allow the composition to be mixed or remixed on shaking. That is, it has fluid or semi fluid properties. In some very limited cases possibly aided by the presence of silicone it may exceptionally be possible to have a foamable composition which is flowable but not apparently shakable.
  • a breakable foam is one that is thermally stable, yet breaks under sheer force.
  • the breakable foam of the present invention is not "quick breaking", i.e., it does not readily collapse upon exposure to body temperature environment. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability, since it allows comfortable application and well directed administration to the target area.
  • a composition of the present invention includes one or more additional components.
  • additional components include but are not limited to anti perspirants, anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, hair conditioners, humectants, pearlescent aids, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, protectants, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking agents, sunless tanning agents, viscosity modifiers and vitamins.
  • a specific additional component may have more than one activity, function or effect.
  • Suitable propellants include volatile hydrocarbons such as butane, propane, isobutane and fluorocarbon gases, or mixtures thereof.
  • the propellant makes up about 3-25 wt% of the foamable composition.
  • the propellants are used to generate and administer the foamable composition as a foam.
  • the total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable composition.
  • Such propellants include, but are not limited to, hydrofluorocarbon (HFC) propellants, which contain no chlorine atoms, and as such, fall completely outside concerns about stratospheric ozone destruction by chlorofluorocarbons or other chlorinated hydrocarbons.
  • HFC hydrofluorocarbon
  • Exemplary non-flammable propellants according to this aspect of the invention include propellants made by DuPont under the registered trademark Dymel, such as 1 ,1,1 ,2 tetrafluorethane (Dymel 134), and 1 ,1,1 ,2,3,3,3 heptafluoropropane (Dymel 227).
  • HFCs possess Ozone Depletion Potential of 0.00 and thus, they are allowed for use as propellant in aerosol products.
  • foamable emulsions including HFC as the propellant can be improved in comparison with the same composition made with a hydrocarbon propellant.
  • foamable compositions comprise a combination of a HFC and a hydrocarbon propellant such as n-butanee or mixtures of hydrocarbom propellants such as propane , ispbutane and butane.
  • a hydrocarbon propellant such as n-butanee or mixtures of hydrocarbom propellants such as propane , ispbutane and butane.
  • Suitable propellents include volatile hydrocarbons such as butane, propane, isobutane and fluorocarbon gases, or mixtures thereof.
  • the propellant makes up about 5-25 wt% of the foamable composition.
  • the propellants are used to generate and administer the foamable composition as a foam.
  • the total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable composition.
  • modulating agent is used to describe an agent which can improve the stability of or stabilize a foamable carrier or composition and or an active agent by modulating the effect of a substance or residue present in the carrier or composition.
  • the modulating agent is used in a water in oil or oil in water emulsion. In one or more other embodiments the modulating agent is used in a unique waterless emulsion.
  • the substance or residue may for example be acidic or basic and potentially alter pH in an emulsion environment or it may be one or more metal ions which may act as a potential catalyst in an emulsion environment.
  • the substance or residue may for example be acidic or basic and potentially alter an artificial pH in a waterless or substantially non aqueous environment or it may be one or more metal ions which may act as a potential catalyst in a waterless or substantially non aqueous environment.
  • the modulating agent is used to describe an agent which can affect pH in an aqueous solution.
  • the agent can be any of the known buffering systems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound.
  • the modulating agent is used to describe an agent, which is a chelating or sequestering or complexing agent that is sufficiently soluble or functional in the solvent to enable it to "mop up” or “lock” metal ions.
  • modulating agent is used to describe an agent which can effect pH in an aqueous solution
  • modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basesity balance of an emulsion carrier, composition, foamable carrier or foamable composition or resultant foam of the present invention.
  • modulating agent is used to describe an agent which can effect pH in an aqueous solution
  • modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basesity balance of a waterless or substantially non aqueous carrier, composition, foamable carrier or foamable composition or resultant foam of the present invention.
  • the substance or residue can be introduced into the formulation from any one or more of the ingredients, some of which themselves may have acidic or basic properties.
  • the polymer or solvent may contain basic residues in which case it may be desirable or beneficial to add an acid.
  • the surfactant may contain some acid residues in which case the addition of a base may be desirable and beneficial.
  • more than one ingredient may contain residues which may ameliorate or compound their significance. For example if one ingredient provided weak acid residues and another stronger acid residues the pH in an emulsion environment (or artificial pH in a waterless environment) should be lower. In contrast if one residue was acid and the other basic the net effect in the formulation maybe significantly reduced.
  • the active ingredient may favor an acidic pH or more significantly may need to be maintained at a certain acidic pH otherwise it may readily isomerize, chemically react or breakdown, in which case introducing acidic components such as an acidic polymer might be of help.
  • sufficient modulating agent is added to achieve a pH in which the active agent is preferably stable.
  • sufficient modulating agent is added to achieve an artificial pH in which the active agent is preferably stable.
  • a buffer as defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525 (1922)], is "a substance which by its presence in solution increases the amount of acid or alkali that must be added to cause unit change in pH.”
  • a buffer solution is a solution of a definite pH made up in such a way that this pH alters only gradually with the addition of alkali or acid. Such a solution consists of a solution of a salt of the week acid in the presence of the three acid itself. The pH of the solution is determined by the dissociation equilibrium of the free acid.
  • An acid can be a strong acid or a weak acid.
  • a strong acid is an acid, which is a virtually 100% ionized in solution.
  • a week acid is one which does not ionize fully. When it is dissolved in water. The lower the value for pKa, the stronger is the acid and likewise, the higher the value for pKa the weaker is the acid.
  • a base can be a strong base or a weak base.
  • a strong base is something, which is fully ionic with 100% hydroxide ions.
  • a weak base is one which does not convert fully into hydroxide ions in solution. The lower the value for pKb, the stronger is the base and likewise, the higher the value for pKb the weaker is the base.
  • the modulating agent comprises an organic compound.
  • the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N I ,N 1 -tetraacetic acid (EGTA), trans-i ⁇ -diaminocyclohexane-N.N.N'.N'-tetraacetic acid (CyDTA) or a pharmaceutically acceptable salt thereof (normally as a sodium salt), more preferably EDTA, HEDTA and their salts; most preferably EDTA and its salts.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • HEDTA hydroxyethylenediaminetriacetic acid
  • NTA nitrilotriace
  • a preferred non limiting example of the chelating agent is EDTA.
  • the chelating and sequestering agent is present in the composition at a level of up to about 5.0%, preferably 1.0 percent, by weight, of the composition.
  • the modulating agent may also be a preservative or an antioxidant or an ionization agent. Any preservative, antioxidant or ionization agents suitable for pharmaceutical or cosmetic application may be used. Non limiting examples of antioxidants are tocopherol succinate, propyl galate, butylated hydroxy toluene and butyl hydroxy anisol. Ionization agents may be positive or may be negative depending on the environment and the active agent or composition that is to be protected. Ionization agents may for example act to protect or reduce sensitivity of active agents.
  • Non limiting examples of positive ionization agents are benzyl conium chloride, and cetyl pyridium chloride.
  • Non limiting examples of negative ionization agents are sodium lauryl sulphate, sodium lauryl lactylate and phospholipids. Heumectant
  • a heumectant is a substance that helps retain moisture and also prevents rapid evaporation.
  • Non limiting examples are propylene glycol, propylene glycol derivatives, glycerin, hydrogenated starch hydrosylate, hydrogenated lanolin, lanolin wax, D manitol, sorbitol, sodium 2-pyrrolidone-5- carboxylate, sodium lactate, sodium PCA, soluble collagen, dibutyl phthalate, and gelatin.
  • Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower.
  • a moisturizer is a substance that helps retain moisture or add back moisture to the skin.
  • examples are allantoin, petrolatum, urea, lactic acid, sodium PCV, glycerin, shea butter, caprylic/capric/stearic triglyceride, candelilla wax, propylene glycol, lanolin, hydrogenated oils, squalene, sodium hyaluronate and lysine PCA.
  • Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower.
  • compositions of the present invention may in one or more embodiments usefully comprise in addition a heumectant or a moisturizer or combinations thereof.
  • a "polar solvent” is an organic solvent, typically soluble in both water and oil. Certain polar solvents, for example propylene glycol and glycerin, possess the beneficial property of a heumectant.
  • the polar solvent is a heumectant.
  • the polar solvent is a polyol.
  • Polyols are organic substances that contain at least two hydroxy groups in their molecular structure.
  • the polar solvent contains an diol (a compound that contains two hydroxy groups in its molecular structure), such as propylene glycol (e.g., 1 ,2-propylene glycol and 1 ,3-propylene glycol), butaneediol (e.g., 1,4-butaneediol), butaneediol (e.g., 1 ,3-butaneediol and 1,4- butenediol), butynediol, pentanediol (e.g., 1,5-pentanediol), hexanediol (e.g., 1 ,6- hexanediol), octanediol (e.g., 1 ,8-o
  • the polar solvent contains a triol (a compound that contains three hydroxy groups in its molecular structure), such as glycerin and 1 ,2,6-Hexanetriol.
  • a triol a compound that contains three hydroxy groups in its molecular structure
  • polar solvents include pyrrolidones, (such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethyl isosorbide, 1 ,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethyl proxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such as lactic acid and glycolic acid.
  • pyrrolidones such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone
  • dimethyl isosorbide 1 ,2,6-hexapetriol
  • DMSO dimethyl sulfoxide
  • DMAc dimethylacetamide
  • alpha hydroxy acids such as lactic acid and glycolic acid.
  • the polar solvent is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature, including PEG200 (MW (molecular weight) about 190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MW about 570- 630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
  • PEG200 MW (molecular weight) about 190-210 kD
  • PEG300 MW about 285-315 kD
  • PEG400 MW about 380-420 kD
  • PEG600 MW about 570- 630 kD
  • higher MW PEGs such as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
  • Polar solvents are known to enhance the penetration of active agent into the skin and through the skin, and therefore, their inclusion in the composition of the present invention can be desirable, despite their undesirable skin drying and irritation potential.
  • Lower molecular weight alcohols can sometimes be more potent as a solvent, for example by extracting lipids from the skin layers more effectively, which characteristic can adversely affect the skin structure and cause dryness and irritation. Therefore the selection of lower molecular weight alcohols is ideally avoided.
  • a “skin penetration enhancer”, also termed herein “penetration enhancer,” is an organic solvent, typically soluble in both water and oil.
  • penetration enhancer include polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1 -menthol, dioxolane, ethylene glycol, hexylene glycol, other glycols, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, dimethylisosorbide, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), azone (1-dodecylaza
  • the penetration enhancer is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature
  • the foamable composition includes a potent solvent, in addition to or in place of one of the hydrophobic solvents, polar solvents or emollients of the composition.
  • a potent solvent is a solvent other than mineral oil that solubilizes a specific active agent substantially better than a hydrocarbon solvent such as mineral oil or petrolatum.
  • a potent solvent solubilizes the active agent 5 fold better than a hydrocarbon solvent; or even solubilizes the active agent 10-fold better than a hydrocarbon solvent.
  • the composition includes at least one active agent in a therapeutically effective concentration; and at least one potent solvent in a sufficient amount to substantially solubilize the at least one active agent in the composition.
  • substantially soluble means that at least 95% of the active agent has been solubilized, i.e., 5% or less of the active agent is present in a solid state.
  • the concentration of the at least one potent solvent is more than about 40% of the at least one solvent of the composition of the present invention; or even more than about 60%.
  • Non-limiting examples of pairs of active agent and potent solvent include: Betamethasone valerate: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1 % in glycofurol; Hydrocortisone butyrate: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1% in glycofurol; Metronidazole: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1% in dimethyl isosrbide; Ketoconazole: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1 % in glycofurol, propylene glycol and dimethyl isosrbide; Mupirocin: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1% in glycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol and polyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidal anti-inflammatory agent: Practically insoluble in mineral oil ( ⁇ 0.001%); soluble
  • a non-limiting exemplary list of solvents that can be considered as potent solvents includes polyethylene glycol, propylene glycol, hexylene glycol, butaneediols and isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl caprylate, diisopropyl adipate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, isosorbide derivatives, such as dimethyl isosorbide, glycofurol and ethoxydiglyco! (transcutol) and laurocapram .
  • a potent solvent in a foam composition provides an improved method of delivering poorly soluble therapeutic agents to a target area. It is known that low drug solubility results in poor bioavailability, leading to decreased effectiveness of treatment. Foam compositions of the present invention, for which the solvent includes a potent solvent, increase the levels of the active agent in solution and thus, provide high delivery and improved therapy.
  • Potent solvents as defined herein, are usually liquid. Formulations comprising potent solvents and active agents are generally disadvantageous as therapeutics, since their usage involves unwanted dripping and inconvenient method of application; resulting in inadequate dosing. Surprisingly, the foams of the present invention, which are drip-free, provide a superior vehicle for such active agents, enabling convenient usage and accurate effective dosing.
  • the foamable pharmaceutical composition may additionally include a mixture of two or more of the solvents selected from the group of hydrophobic solvents, silicone oils, emollients, polar solvents and potent solvents in an appropriate proportion as would be appreciated to a person skilled in the art.
  • the PPG alkyl ether may act as a potent solvent
  • a pharmaceutical or cosmetic composition manufactured using the foamable carrier of the present invention is very easy to use. When applied onto the afflicted body surface of mammals, i.e., humans or animals, it is in a foam state, allowing free application without spillage. Upon further application of a mechanical force, e.g., by rubbing the composition onto the body surface, it freely spreads on the surface and is rapidly absorbed.
  • the foamable composition of the present invention is stable, having an acceptable shelf-life of at least one year, or preferably, at least two years at ambient temperature, as revealed in accelerated stability tests.
  • the foamable compositions according to the present invention are stable. Following accelerated stability studies, they demonstrate desirable texture; they form fine bubble structures that do not break immediately upon contact with a surface, spread easily on the treated area and absorb quickly.
  • composition should also be free flowing, to allow it to flow through the aperture of the container, e.g., and aerosol container, and create an acceptable foam.
  • Foam quality can be graded as follows:
  • Grade E excellent: very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure; does not rapidly become dull; upon spreading on the skin, the foam retains the creaminess property and does not appear watery.
  • Grade G (good): rich and creamy in appearance, very small bubble size, "dulls” more rapidly than an excellent foam, retains creaminess upon spreading on the skin, and does not become watery.
  • Grade FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable; upon spreading on the skin the product dulls rapidly and becomes somewhat lower in apparent viscosity.
  • Grade F very little creaminess noticeable, larger bubble structure than a "fairly good” foam, upon spreading on the skin it becomes thin in appearance and watery.
  • Grade P no creaminess noticeable, large bubble structure, and when spread on the skin it becomes very thin and watery in appearance.
  • Grade VP dry foam, large very dull bubbles, difficult to spread on the skin.
  • Topically administrable foams are typically of quality grade E or G, when released from the aerosol container. Smaller bubbles are indicative of more stable foam, which does not collapse spontaneously immediately upon discharge from the container. The finer foam structure looks and feels smoother, thus increasing its usability and appeal.
  • the breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability. Thermally sensitive foams immediately collapse upon exposure to skin temperature and, therefore, cannot be applied on the hand and afterwards delivered to the afflicted area.
  • foams Another property of the foam is specific gravity, as measured upon release from the aerosol can.
  • foams typically have specific gravity of less than 0.12 g/mL; or less than 0.10 g/mL; or less than 0.08 g/mL, depending on their composition and on the propellant concentration.
  • the foamable carrier of the present invention is an ideal vehicle for active pharmaceutical ingredients and active cosmetic ingredients.
  • active pharmaceutical ingredients and active cosmetic ingredients are collectively termed “active agent” or “active agents”.
  • Suitable active agents include but are not limited to active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents
  • foamable carrier of the present invention is suitable for treating any inflicted surface.
  • foamable carrier is suitable for administration to the skin, a body surface, a body cavity or mucosal surface, e.g., the cavity and/or the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum (severally and interchangeably termed herein "target site").
  • the foamable composition of the present invention is useful in treating an animal or a human patient having any one of a variety of dermatological disorders, including dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma,
  • the foamable composition of the present invention is suitable for treating a disorder of a body cavity or mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum.
  • Non limiting examples of such conditions include chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the vagina, vaginal dryness, dyspareuni
  • the composition is useful for the treatment of an infection.
  • the composition is suitable for the treatment of an infection, selected from the group of a bacterial infection, a fungal infection, a yeast infection, a viral infection and a parasitic infection.
  • the composition is useful for the treatment of wound, ulcer and burn.
  • the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.
  • composition of the present invention is also suitable for administering a hormone to the skin or to a mucosal membrane or to a body cavity, in order to deliver the hormone into the tissue of the target organ, in any disorder that responds to treatment with a hormone.
  • the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.
  • the disorder is selected from the group consisting of dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin infections, warts, moHuscum contagiosum, trauma or injury to the skin, postoperative or post-surgical skin conditions, scabies
  • the disorder is psoriasis;
  • the active agent is a vitamin D derivative, given at a concentration between about 0.001% and about 0.02% by weight.
  • the active agent is selected from the group comprising of: Hydrocortisone acetate, Betamethasone valerate, Clobetasol proprionate, Acyclovir, Ciclopirox, Clindamycin, Azelaic acid, Metronidazol, Diclofenac, Tacrolimus, Caffeine, Clotrimazole, Lidocaine base, Terbinafine HCL, Gentamycin, Dexpanthenol, Urea, Ammonium lactate, Povidone-iodine and Permethrine.
  • the active agent is a permethrin.
  • the active agent is a permethrin.
  • the foamable compositions and foams are suitable for use in treating, ameliorating, reducing or preventing a dermatological, cosmetic or mucosal disorder. More particularly, they are suitable for use where such disorders would otherwise be less responsive when treated with one agent alone.
  • Each aerosol canister is filled with PFF and crimped with valve using vacuum crimping machine. Pressurizing
  • Pressurizing is carried out using a hydrocarbon gas or gas mixture Canisters are filled and then warmed for 30 sec in a warm bath at 50 0 C and well shaken immediately thereafter. Closure Integrity Test.
  • Each pressurized canister is subjected to bubble and crimping integrity testing by immersing the canister in a 60 0 C water bath for 2 minutes. Canisters are observed for leakage as determined by the generation of bubbles. Canisters releasing bubbles are rejected. TESTS
  • LFRA100 instrument is used to characterize hardness.
  • a probe is inserted into the test material.
  • the resistance of the material to compression is measured by a calibrated load cell and reported in units of grams on the texture analyzer instrument display.
  • Preferably at least three repeat tests are made.
  • the textural characteristics of a dispensed foam can effect the degree of dermal penetration, efficacy, spreadability and acceptability to the user. The results can also be looked at as an indicator of softness. Note: the foam sample is dispensed into an aluminum sample holder and filled to the top of the holder. [0154] Collapse Time
  • Collapse time is examined by dispensing a given quantity of foam and photographing sequentially its appearance with time during incubation at 36°C. It is useful for evaluating foam products, which maintain structural stability at skin temperature for at least 1 min.
  • Viscosity is measured with Brookfield LVDV-II + PRO with spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM. Viscosity is usually measured at
  • the viscosity at 1RPM may be measured, although the figures are of a higher magnitude.
  • the centrifugation used in this procedure serves as a stress condition simulating the aging of the liquid dispersion under investigation. Under these conditions, the centrifugal force applied facilitates the coalescence of dispersed globules or sedimentation of dispersed solids, resulting in loss of the desired properties of the formulated dispersion.
  • Example 1 Foamable oil in water emulsion vehicle compositions, containing high concentrations (more than 15% and up to 60%) PPG alky ether
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • - Good quality foams can be prepared from aqueous compositions containing 45% PPG with a single surfactant.
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • - Good foams can be prepared from aqueous compositions containing 60% PPG and only about 30% of water.
  • aqueous oil in water formulation containing GMS (Surfactant) and CMC (polymer) produced an good foam as did a similar formulation with other surfactants but no polymer.
  • a foam containing very high amounts of PPG can be prepared with or without polymer.
  • Example 2 Waterless Foamable vehicle compositions, containing high concentrations (UP to 83%) PPG alky ether
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • - Good foams can be prepared from substantially waterless compositions containing over 74% PPG.
  • a waterless foam containing very high amounts of PPG can be prepared, wherein PPG is the main solvent, with a foam adjuvant and solid triglycerides (cocoglycerides) and a stabilizing surfactant (GMS glyceryl stearate)
  • PPG is the main solvent
  • a foam adjuvant and solid triglycerides cocoglycerides
  • a stabilizing surfactant GMS glyceryl stearate
  • Example 3 Foamable oil in water emulsion vehicle compositions, containing PPG alky ether
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • compositions contain a variety of organic carriers, in addition to the PPG alkyl ether. In the majority of the compositions the surface active agents are solely non- ionic.
  • the formulations contain polar solvents, which contribute to skin penetration of an active agent.
  • Formula 1 was found to be non flammable when subjected to an aerosol inflammability test which was performed dalong the lines of European Standard prEN 14851 , titled "Aerosol containers - Aerosol foam flammability test" although in a simplified form. According to this standard, a product is considered inflammable if a stable flame appears following ignition, which is at least 4 cm high and which is maintained for at least 2 seconds. Approximately 5 g of foam, mousse gel or paste is sprayed from the aerosol container on to a watchglass. An ignition source (a lighter) was placed at the base of the watchglass and any ignition and sustained combustion of the foam, mousse, gel or paste was observed.
  • An ignition source a lighter
  • the test was carried out in a draught-free environment capable of ventilation, with the temperature controlled at 20 ⁇ 5°C and relative humidity in the range of 30% to 80%. According to the standard, appearance of a stable flame which is at least 4 cm high and which is maintained for at least 2 seconds defines a product as "inflammable.”
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • compositions contain a variety of organic carriers, in addition to the PPG alkyl ether.
  • the surface active agents are solely non- ionic.
  • the formulations contain polar solvents, which contribute to skin penetration of an active agent.
  • Example 5 Foamable oil in water emulsion vehicle compositions, containing PPG alky ether and a vitamin D derivative (3%, 10% and 15% PPG)
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • compositions contain a variety of organic carriers, in addition to the PPG alkyl ether.
  • the surface active agents are solely non- ionic.
  • the formulations contain polar solvents, which contribute to skin penetration of an active agent.
  • Example 6 Foamable oil in water emulsion vehicle compositions, containing PPG alky ether and Permethrin
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • compositions contain a variety of organic carriers, in addition to the PPG alkyl ether.
  • the permethrin concentration can range between about 1% and about 8%.
  • the surface active agents are solely non- ionic.
  • the formulations contain polar solvents, which contribute to skin penetration of an active agent.
  • Example 7 oil in water Foamable compositions comprising PPG
  • Ceteareth-20 1.60 — 1.60 ⁇ — 1.50 Seteareth-21 2.20 2.00 1.50 — 1.50 2.20
  • Pemulen TR2 0.05 — 0.05 — — — — — —
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • the surface active agents are solely non- ionic.
  • Example 8 waterless PPG Foamable compositions having small amounts of PPG ( ⁇ 15%)
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • the liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • Example 9 Theoretical Aqueous PPG formulations with Active Agent
  • Exemplary concentrations of active agents in foamable compositions are set out in Table 2. Each active agent is added into, for example, any of the carriers listed in any of the above aqueous Examples in a therapeutically effective concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w as appropriate by water.
  • Example 10 Theoretical Non Aqueous PPG formulations with Active Agent
  • concentrations of active agents in foam able compositions are set out in Table 2 above. Each active agent is added into, for example, any of the carriers listed in any of the above Non Aqueous Examples in a therapeutically effective concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w as appropriate by solvent or petrolatum.
  • Example 11 Theoretical of Substantially Non Aqueous PPG formulations with Active Agent
  • Exemplary concentrations of active agents in foamable compositions are set out in Table 2 above. Each active agent is added into, for example, any of the carriers listed in any of the above substantially Non Aqueous Examples in a therapeutically effective concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w as appropriate by water, solvent or petrolatum.

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EP07848880A 2006-06-07 2007-06-07 Schäumbare trägersubstanz mit polypropylenglycolalkylether und pharmazeutische zusammensetzungen daraus Withdrawn EP2029106A2 (de)

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US81162706P 2006-06-07 2006-06-07
US11/481,596 US8119150B2 (en) 2002-10-25 2006-07-06 Non-flammable insecticide composition and uses thereof
US11/488,989 US10117812B2 (en) 2002-10-25 2006-07-19 Foamable composition combining a polar solvent and a hydrophobic carrier
US11/717,897 US8119109B2 (en) 2002-10-25 2007-03-13 Foamable compositions, kits and methods for hyperhidrosis
PCT/IB2007/003463 WO2008038140A2 (en) 2006-06-07 2007-06-07 Foamable vehicle comprising polypropylene glycol alkyl ether and pharmaceutical compositions thereof

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